Genomic Biomarker-Selected Therapy for Prostate Cancer

(GUNS Trial)

Recruiting at 8 trial locations

Overseen By Tiiu Sildva, PhD

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: University of British Columbia

Must be taking: LHRHa, Apalutamide

Must not be taking: Androgens, Estrogens

Disqualifiers: T4 prostate cancer, Hypogonadism, HIV, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 7

315 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if targeting prostate cancer treatment based on specific genetic markers in the tumor can improve patient outcomes. Initially, all participants will receive two drugs: apalutamide (also known as Erleada) and a hormone treatment (luteinizing hormone-releasing hormone agonist, or LHRHa), while researchers study the tumor's genetics. Based on these results, participants will be placed in different groups to test additional treatments. The trial seeks men with high-risk prostate cancer who have not received prior treatment for this condition. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications for this trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot have received more than 30 days of certain prostate cancer treatments before joining the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the treatments under study have varying safety levels based on past trials and uses. Here's a breakdown:

1. **LHRHa plus Apalutamide**: Studies indicate that combining LHRHa (a hormone therapy) with apalutamide (a hormone-blocking drug) is generally well-tolerated. Apalutamide does not seem to increase side effects and helps maintain quality of life.

2. **LHRHa plus Apalutamide plus Abiraterone Acetate plus Prednisone**: This combination shows promise for treating prostate cancer. While it can cause side effects, the medications are generally safe. Both apalutamide and abiraterone acetate have FDA approval for similar uses, supporting their safety.

3. **LHRHa plus Abiraterone Acetate plus Prednisone**: This combination is FDA-approved for certain prostate cancers. It effectively lowers testosterone levels, aiding treatment. Its safety is well-documented and generally manageable.

4. **LHRHa plus Abiraterone Acetate plus Prednisone plus Docetaxel**: Adding docetaxel, a chemotherapy drug, may increase side effects but is known to improve survival in prostate cancer patients. This combination is used in practice, indicating a good understanding of its safety.

5. **LHRHa plus Abiraterone Acetate plus Prednisone plus Niraparib**: This newer combination shows promising early study results. While still under evaluation, the individual drugs are known, and research supports their combined use.

6. **LHRHa plus Apalutamide plus Atezolizumab**: Atezolizumab is an immunotherapy drug. Researchers are exploring its combination with apalutamide and LHRHa. Apalutamide's FDA approval for nonmetastatic prostate cancer suggests its safety.

Overall, these treatments are in a phase that checks for effectiveness and confirms safety. While each can have side effects, research suggests they are generally well-tolerated. Always consult a healthcare provider to understand what this means personally. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for prostate cancer because they explore new combinations of existing therapies, potentially enhancing effectiveness. Unlike the standard hormonal therapies targeting androgen receptors, these investigational treatments include drugs like abiraterone acetate and apalutamide, which block androgen production and receptor signaling, respectively. Some combinations also incorporate novel agents like niraparib, a PARP inhibitor, and atezolizumab, an immunotherapy drug. These additions aim to tackle cancer from multiple angles, offering hope for improved outcomes beyond the usual hormonal or chemotherapy options, like docetaxel alone.

What evidence suggests that this trial's treatments could be effective for prostate cancer?

In this trial, participants will join different treatment groups to evaluate the effectiveness of various combinations for prostate cancer. Previous studies have shown that combining luteinizing hormone-releasing hormone agonists (LHRHa) with apalutamide improves survival rates in prostate cancer patients. In Group 1b, participants will receive LHRHa, apalutamide, abiraterone acetate, and prednisone, which previous research suggests can significantly delay cancer progression. Group 2b will receive LHRHa, abiraterone acetate, prednisone, and docetaxel, a combination shown to extend survival compared to standard treatments alone. Group 3 will explore adding niraparib to abiraterone and prednisone, which has been associated with a significant delay in cancer progression. Lastly, Group 4 will investigate the combination of apalutamide with atezolizumab, which has shown promise in past studies, although it did not improve specific pathological outcomes. Overall, these findings support the potential effectiveness of these treatment combinations for prostate cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Martin E Gleave, MD

Principal Investigator

University of British Columbia

Are You a Good Fit for This Trial?

Men over 18 with high-risk localized prostate cancer, no prior treatments for it, and willing to undergo genetic testing. They must have a life expectancy of at least 3 years and be in good health otherwise. Men with severe diseases, allergies to study drugs, or who can't take oral meds are excluded.

Inclusion Criteria

I have less than 3 metastases visible by PSMA imaging and am a candidate for radical prostatectomy.

My prostate cancer is considered high-risk.

Participant consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each participant must sign a consent form prior to enrolment in the trial to document their willingness to participate

Exclusion Criteria

M1 by conventional imaging (CT, bone scan)

My prostate cancer is advanced (Stage T4) as confirmed by tests.

You have had an allergic reaction to any of the study drugs or any of the substances used to make them.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction

Participants receive LHRHa plus apalutamide while genomic sequencing is performed

8 weeks

2 visits (in-person)

Sub-protocol Treatment

Participants are assigned to a treatment arm based on genomic profiling results

16 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 years

Annual visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Abiraterone Acetate 250mg
• Apalutamide
• Docetaxel
• Luteinizing hormone-releasing hormone agonist (LHRHa)
• Niraparib 100mg Oral Capsule
• Prednisone 5mg Tab

Trial Overview The trial tests if targeted therapy based on genomic profiling improves response in men with prostate cancer. After initial treatment with hormone therapy plus apalutamide, participants may receive additional drugs like abiraterone acetate and prednisone, docetaxel or niraparib depending on their tumor's genetics.

How Is the Trial Designed?

Group I: Group 1b Active Control 3 Interventions

LHRHa plus apalutamide plus abiraterone acetate plus prednisone.

Group II: Group 1a Active Control 1 Intervention

LHRHa plus apalutamide.

Group III: Group 2a Active Control 2 Interventions

LHRHa plus abiraterone acetate plus prednisone.

Group IV: Group 2b Active Control 3 Interventions

LHRHa plus abiraterone acetate plus prednisone plus docetaxel.

Group V: Group 3 Active Control 3 Interventions

LHRHa plus abiraterone acetate plus prednisone plus niraparib

Group VI: Group 4 Active Control 2 Interventions

LHRHa plus apalutamide plus atezolizumab

Apalutamide is already approved in United States, European Union for the following indications:

Approved in United States as Erleada for:

• Non-metastatic castration-resistant prostate cancer (nmCRPC)
• Metastatic castration-sensitive prostate cancer (mCSPC)

Approved in European Union as Erleada for:

• Non-metastatic castration-resistant prostate cancer (nmCRPC)
• Metastatic castration-sensitive prostate cancer (mCSPC)

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Janssen Inc.

Industry Sponsor

Trials

24

Recruited

8,100+

University Health Network, Toronto

Collaborator

Trials

1,555

Recruited

526,000+

Published Research Related to This Trial

This clinical trial aims to evaluate the efficacy and safety of apalutamide in 110 patients with metastatic castration-resistant prostate cancer, focusing on the primary outcome of prostate-specific antigen (PSA) response rate, defined as a ≥50% decline from baseline at 12 weeks.

The study will also assess various secondary outcomes, including time to PSA progression and overall survival, while monitoring for any grade 3 or 4 adverse events, ensuring a comprehensive evaluation of both effectiveness and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of apalutamide in patients with metastatic castration-resistant prostate cancer (GENESIS): protocol for a multicentre, open-label, single-arm clinical trial. Miyake, H., Kakei, Y., Nakano, Y., et al.[2023]

In a study of 68 patients with metastatic prostate cancer, both leuprolide and triptorelin effectively reduced plasma testosterone levels, with leuprolide showing a faster decrease at 1 month.

While both treatments were effective in lowering testosterone, there were no significant differences in clinical efficacy or overall safety between the two LHRH analogues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Tolerance and clinical and biological responses during the first 6 months of treatment with 1-month sustained release LHRH agonists leuprolerin and triptolerin in patients with metastatic prostate cancer]. Abbou, CC., Lucas, C., Leblanc, V.[2018]

GnRH antagonists provide faster suppression of hormones like luteinising hormone and testosterone compared to GnRH agonists, leading to improved disease control in advanced prostate cancer.

Patients receiving GnRH antagonists have a significantly lower risk of cardiac events within one year of treatment initiation, making them a safer option for men with pre-existing cardiovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of gonadotrophin-releasing hormone antagonists in the treatment of patients with advanced hormone-dependent prostate cancer in the UK. Rosario, DJ., Davey, P., Green, J., et al.[2022]

Degarelix, a GnRH receptor antagonist, significantly reduces prostate cancer cell viability compared to controls, while leuprolide, a GnRH agonist, can stimulate cell growth in the same cancer cell lines.

In animal studies, degarelix effectively lowers testosterone levels and tumor size compared to leuprolide, suggesting it may offer a more effective treatment option for managing prostate cancer without the 'testosterone flare' associated with LHRH agonists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GnRH Antagonists Have Direct Inhibitory Effects On Castration-Resistant Prostate Cancer Via Intracrine Androgen and AR-V7 Expression. Cucchiara, V., Yang, JC., Liu, C., et al.[2020]

Apalutamide effectively blocks androgen receptor signaling in metastatic hormone-sensitive prostate cancer, leading to a rapid decrease in PSA levels and increased testosterone during monotherapy, indicating its efficacy in treatment.

Administering apalutamide 1 hour before GnRH agonists not only simplifies the treatment process but also effectively prevents testosterone flare-up, achieving castration levels of testosterone by day 28 without worsening side effects like dysuria or bone pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absence of PSA Flare With Apalutamide Administered 1 Hour in Advance With GnRH Agonists: Case Report. Hu, Z., Liu, Z., Chen, Z., et al.[2022]

In a study involving 39 patients with localized prostate cancer, neoadjuvant treatment with degarelix alone resulted in significantly higher levels of intratumoral dihydrotestosterone (DHT) compared to combinations of degarelix with bicalutamide or LHRH agonist with bicalutamide, suggesting a unique mechanism of action for degarelix.

Patients receiving degarelix had lower serum follicle-stimulating hormone (FSH) levels after 12 weeks compared to those on LHRH agonist, indicating potential advantages in hormonal regulation during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II, Randomized, Open-Label Study of Neoadjuvant Degarelix versus LHRH Agonist in Prostate Cancer Patients Prior to Radical Prostatectomy. Sayyid, RK., Evans, A., Hersey, K., et al.[2017]

In a study of 242 prostate cancer patients, abarelix depot was found to prevent testosterone surges during the first week of treatment, unlike LH-RH agonists, which caused an 82% surge rate.

Abarelix depot achieved medical castration in 75% of patients within the first week, demonstrating faster efficacy and better tolerability compared to LH-RH agonists, which had no such rapid effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. Tomera, K., Gleason, D., Gittelman, M., et al.[2017]

In the SPARTAN study involving 1207 patients with nonmetastatic castration-resistant prostate cancer, apalutamide significantly improved health-related quality of life (HRQoL) compared to placebo, with patients maintaining better scores over time.

Patients receiving apalutamide experienced minimal side effects and reported no worsening of fatigue, while those on placebo showed a decline in quality of life after about one year, highlighting the efficacy and tolerability of apalutamide in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy. Oudard, S., Hadaschik, B., Saad, F., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38388778/

Updated 5-year results for short course abiraterone acetate ... Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years.

2. redjournal.org redjournal.org/article/S0360-3016(21)01772-7/fulltext

Five Year Results of Short Course Complete Androgen ... All men were treated with 6 months of abiraterone acetate (1000mg daily), prednisone (5mg daily), and depot LHRH agonist initiated 8 weeks prior ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMe1704992

Improved Outcomes in Men with Advanced Prostate Cancer Confidence in the conclusion stems from the observation that treatment with abiraterone plus an LHRH agonist was superior to an LHRH agonist alone in these two ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e17044

Survival results from a single-arm, phase II study. AAP used alone following GnRH discontinuation in pts with mPC successfully suppressed T and produced encouraging survival outcomes with an acceptable safety ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9705242/

LHRH sparing therapy in patients with chemotherapy-naïve ... Recent results indicated that treatment with abiraterone acetate (AA) plus prednisone (P) further suppresses serum testosterone levels over ADT alone.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11667785/

Luteinizing hormone-releasing hormone receptor agonists ... A drug safety evaluation of abiraterone acetate in the treatment of prostate cancer. Expert Opin Drug Saf. 2019;18:759–67. doi: 10.1080 ...

7. medsafe.govt.nz medsafe.govt.nz/profs/datasheet/z/zytigatab.pdf

ZYTIGA® - abiraterone acetate NEW ZEALAND DATA ... ZYTIGA is also indicated with prednisone or prednisolone for: • the treatment of patients with metastatic castration resistant prostate cancer (mCRPC) who are ...

8. innovativemedicine.jnj.com innovativemedicine.jnj.com/australia/download/zytiga-pi.pdf

Australian Product Information - ZYTIGA® (abiraterone ... Abiraterone decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRH agonists alone or by orchiectomy. Prostate ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT01946165?term=abiraterone%20acetate&viewType=Table&rank=2

Study Details | Abiraterone Acetate Plus LHRH Agonist and ... Abiraterone acetate is FDA approved in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer who have ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5628432/

Abiraterone acetate plus LHRH therapy versus ... The trial will assess radiographic progression-free survival after 12 months of treatment with abiraterone/prednisone in patients who will be ...